Although pancreatic cancer has the highest case fatality rate of any common human malignancy, relatively little progress has been made in its treatment. To develop more effective and less toxic therapies it is necessary to understand the key molecular abnormalities of cancer cells, and to target these specifically. Recent evidence has indicated that inappropriate activation of the transcription factor STAT3 may be critical to the malignant behavior of pancreatic carcinoma cells. We have identified a cohort of genes that are immediate targets of STAT3, and which are activated as a group in primary human pancreatic cancers. In addition, given the central importance of STAT3 in pancreatic cancer pathogenesis, we have developed a high throughput cell based screen for small molecules that can inhibit the function of STAT3. In the present application we propose to elucidate the role that these STAT3 target genes play in pancreatic cancer biology, and evaluate the molecules we have identified as targeted therapies for this disease. Specifically, we will address three aims: To determine the role of STAT3 target genes in the biology of pancreatic cancer; to elucidate the effect of targeted STAT3 inhibitors on gene expression and phenotype of human pancreatic cancer cells; and, to determine the activity of STAT3 inhibitors in a murine model of pancreatic cancer. Through this work, we aim to enhance our understanding of the molecular underpinnings of pancreatic cancer, and to develop targeted molecular therapy for this disease. Relevance: To enhance the treatment of pancreatic cancer, this proposal will focus on understanding how the abnormal function of a key transcription factor, STAT3, directly contributes to the pathogenesis of this disease. Given the importance of this protein in the biology of pancreatic cancer, we have identified drugs that can specifically inhibit the function of STAT3. We will test these drugs to determine whether they can be prototypes for a novel targeted form of therapy for this disease. [unreadable] [unreadable] [unreadable]